'Irreversible' endothelin-1 binding does not prohibit ABT-627 from reversing endothelin-1-induced effects.

Abstract

Endothelin-1 (ET-1) is thought to play a role in a wide range of pathological conditions. One of the distinct characteristics of ET-1 is its long-lasting vasoconstrictor action, which is presumably caused by the irreversible binding of ET-1 to ET receptors and by the functional effects of internalized ET receptors. ABT-627 is a potent endothelin-A (ET(A))-selective antagonist with a Ki value at 0.034 nM for the human ET(A) receptor, and is currently being used in clinical studies for prostate cancer. Unlike ET-1, the binding of 125I-labeled ABT-627 to human ET(A) receptors expressed in Chinese hamster ovary (CHO) cells is reversible, and the dissociation half-life for the ligand/receptor complex is 2 h. Interestingly, the binding of both ET-1 and ABT-627 to the ET(A)-receptor results in partial receptor internalization but only ET-1 is capable of triggering intracellular functional responses. Although ABT-627 binding to membranes is more reversible than ET-1 binding, ABT-627 is able to reverse an ET-1-induced contraction in rat aortic rings in a dose-dependent manner, and at 1 microM produces nearly complete reversal of the constrictor effects of 10 nM ET-1 within 60 min. Similarly, in vivo studies show that ABT-627 (0.01 and 0.1 mg/kg/min i.v.) reverses the ET-1-induced increase in arterial pressure in anesthetized, ganglionic-blocked rats, and after 60 min, ABT-627 essentially normalizes pressure. Our data show that ABT-627 is capable of reversing an established response induced by ET-1 and is useful in reversing pathological conditions involving ET-1.

• Authors: W J Chiou, J L Wessale, T von Geldern, T J Opgenorth, J R Wu-Wong
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 36 Issue 5 Suppl 1 Pg. S48-52 (Nov 2000) ISSN: 0160-2446 [Print] United States
• PMID: 11078333 (Publication Type: Journal Article)

Chemical References

• Endothelin Receptor Antagonists
• Endothelin-1
• Pyrrolidines
• Receptor, Endothelin A
• Atrasentan

Topics

• Animals
• Atrasentan
• Blood Pressure (drug effects)
• CHO Cells
• Cricetinae
• Dose-Response Relationship, Drug
• Endothelin Receptor Antagonists
• Endothelin-1 (antagonists & inhibitors, pharmacology)
• Humans
• Pyrrolidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Endothelin A